针对三核苷酸重复疾病致病等位基因的定制 RNAi 敲低。
Tailor-made RNAi knockdown against triplet repeat disease-causing alleles.
机构信息
National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.
出版信息
Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21731-6. doi: 10.1073/pnas.1012153107. Epub 2010 Nov 22.
Abstract
Nucleotide variations, including SNPs, in the coding regions of disease genes are important targets for RNAi treatment, which is a promising medical treatment for intractable diseases such as triplet repeat diseases. However, the identification of such nucleotide variations and the design of siRNAs conferring disease allele-specific RNAi are quite difficult. In this study we developed a pull-down method to rapidly identify coding SNP (cSNP) haplotypes of triple repeat, disease-causing alleles, and we demonstrated disease allele-specific RNAi that targeted cSNP sites in mutant Huntingtin alleles, each of which possessed a different cSNP haplotype. Therefore, the methods presented here allow for allele-specific RNAi knockdown against disease-causing alleles by using siRNAs specific to disease-linked cSNP haplotypes, and advanced progress toward tailor-made RNAi treatments for triplet repeat diseases.
摘要
核苷酸变异，包括编码区域的单核苷酸多态性 (SNPs)，是 RNAi 治疗的重要靶点，RNAi 治疗是治疗三核苷酸重复疾病等难治性疾病的一种有前途的医疗方法。然而，这种核苷酸变异的鉴定和设计赋予疾病等位基因特异性 RNAi 的 siRNAs 是相当困难的。在这项研究中，我们开发了一种下拉法来快速鉴定三核苷酸重复、致病等位基因的编码 SNP (cSNP) 单倍型，我们证明了针对突变亨廷顿等位基因中 cSNP 位点的疾病等位基因特异性 RNAi，每个突变等位基因都具有不同的 cSNP 单倍型。因此，这里提出的方法允许使用针对疾病相关 cSNP 单倍型的 siRNAs 对致病等位基因进行特异性 RNAi 敲低，并朝着针对三核苷酸重复疾病的定制 RNAi 治疗取得了先进的进展。
相似文献
1
Tailor-made RNAi knockdown against triplet repeat disease-causing alleles.针对三核苷酸重复疾病致病等位基因的定制 RNAi 敲低。
Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21731-6. doi: 10.1073/pnas.1012153107. Epub 2010 Nov 22.
2
Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington's disease patients.针对三个单核苷酸多态性（SNP）的五种小干扰RNA（siRNA）可为四分之三的亨廷顿舞蹈症患者提供治疗。
Curr Biol. 2009 May 12;19(9):774-8. doi: 10.1016/j.cub.2009.03.030. Epub 2009 Apr 9.
3
Haplotype background, repeat length evolution, and Huntington's disease.单倍型背景、重复长度进化与亨廷顿舞蹈症
Am J Hum Genet. 2009 Dec;85(6):939-42. doi: 10.1016/j.ajhg.2009.11.002.
4
ss-siRNAs allele selectively inhibit ataxin-3 expression: multiple mechanisms for an alternative gene silencing strategy.ss-siRNAs 等位基因选择性抑制 ataxin-3 表达：替代基因沉默策略的多种机制。
Nucleic Acids Res. 2013 Nov;41(20):9570-83. doi: 10.1093/nar/gkt693. Epub 2013 Aug 9.
5
Enhancement of allele discrimination by introduction of nucleotide mismatches into siRNA in allele-specific gene silencing by RNAi.在RNA干扰介导的等位基因特异性基因沉默中，通过在小干扰RNA中引入核苷酸错配来增强等位基因鉴别。
PLoS One. 2008 May 21;3(5):e2248. doi: 10.1371/journal.pone.0002248.
6
Identification and allele-specific silencing of the mutant huntingtin allele in Huntington's disease patient-derived fibroblasts.亨廷顿舞蹈病患者来源的成纤维细胞中突变型亨廷顿蛋白等位基因的鉴定及等位基因特异性沉默
Hum Gene Ther. 2008 Jul;19(7):710-9. doi: 10.1089/hum.2007.116.
7
Haplotype analysis of the CAG and CCG repeats in 21 Brazilian families with Huntington's disease.21 个巴西亨廷顿舞蹈症家系的 CAG 和 CCG 重复序列单体型分析。
J Hum Genet. 2012 Dec;57(12):796-803. doi: 10.1038/jhg.2012.120. Epub 2012 Oct 11.
8
Identification and characterization of the miniature pig Huntington's disease gene homolog: evidence for conservation and polymorphism in the CAG triplet repeat.小型猪亨廷顿舞蹈病基因同源物的鉴定与特征分析：CAG三联体重复序列保守性及多态性的证据
Genomics. 2000 Oct 1;69(1):72-85. doi: 10.1006/geno.2000.6317.
9
Allele-selective inhibition of huntingtin expression by switching to an miRNA-like RNAi mechanism.通过转换为类似miRNA的RNAi机制实现亨廷顿蛋白表达的等位基因选择性抑制。
Chem Biol. 2010 Nov 24;17(11):1183-8. doi: 10.1016/j.chembiol.2010.10.013.
10
A novel measurement of allele discrimination for assessment of allele-specific silencing by RNA interference.一种用于评估RNA干扰介导的等位基因特异性沉默的新型等位基因鉴别测量方法。
Mol Biol Rep. 2014 Nov;41(11):7115-20. doi: 10.1007/s11033-014-3586-7. Epub 2014 Jul 19.
引用本文的文献
1
Development of versatile allele-specific siRNAs able to silence all the dominant dynamin 2 mutations.能够沉默所有显性发动蛋白2突变的通用等位基因特异性小干扰RNA的开发。
Mol Ther Nucleic Acids. 2022 Aug 13;29:733-748. doi: 10.1016/j.omtn.2022.08.016. eCollection 2022 Sep 13.
2
Targeting N-Terminal Huntingtin with a Dual-sgRNA Strategy by CRISPR/Cas9.CRISPR/Cas9 靶向 N 端亨廷顿蛋白的双 sgRNA 策略。
Biomed Res Int. 2019 Nov 16;2019:1039623. doi: 10.1155/2019/1039623. eCollection 2019.
3
Supplemental Treatment for Huntington's Disease with miR-132 that Is Deficient in Huntington's Disease Brain.用在亨廷顿病大脑中缺乏的miR-132对亨廷顿病进行补充治疗。
Mol Ther Nucleic Acids. 2018 Jun 1;11:79-90. doi: 10.1016/j.omtn.2018.01.007. Epub 2018 Feb 2.
4
Protein Misfolding and Aggregation as a Therapeutic Target for Polyglutamine Diseases.蛋白质错误折叠与聚集作为聚谷氨酰胺疾病的治疗靶点
Brain Sci. 2017 Oct 11;7(10):128. doi: 10.3390/brainsci7100128.
5
A novel measurement of allele discrimination for assessment of allele-specific silencing by RNA interference.一种用于评估RNA干扰介导的等位基因特异性沉默的新型等位基因鉴别测量方法。
Mol Biol Rep. 2014 Nov;41(11):7115-20. doi: 10.1007/s11033-014-3586-7. Epub 2014 Jul 19.
6
Allele-specific Gene Silencing of Mutant mRNA Restores Cellular Function in Ullrich Congenital Muscular Dystrophy Fibroblasts.突变型 mRNA 的等位基因特异性基因沉默可恢复先天性肌营养不良症成纤维细胞的细胞功能。
Mol Ther Nucleic Acids. 2014 Jun 24;3(6):e171. doi: 10.1038/mtna.2014.22.
7
Oligonucleotide-based strategies to combat polyglutamine diseases.基于寡核苷酸的多聚谷氨酰胺疾病防治策略。
Nucleic Acids Res. 2014 Jun;42(11):6787-810. doi: 10.1093/nar/gku385. Epub 2014 May 21.
8
Disease-causing allele-specific silencing by RNA interference.通过 RNA 干扰导致致病等位基因特异性沉默。
Pharmaceuticals (Basel). 2013 Apr 11;6(4):522-35. doi: 10.3390/ph6040522.
9
Specific inhibition of tumor cells by oncogenic EGFR specific silencing by RNA interference.通过 RNA 干扰特异性沉默致癌 EGFR 抑制肿瘤细胞。
PLoS One. 2013 Aug 8;8(8):e73214. doi: 10.1371/journal.pone.0073214. eCollection 2013.
10
5' Unlocked Nucleic Acid Modification Improves siRNA Targeting.5' 非锁定核酸修饰可提高 siRNA 靶向性。
Mol Ther Nucleic Acids. 2013 Jul 2;2(7):e103. doi: 10.1038/mtna.2013.36.
本文引用的文献
1
Allele-specific silencing by RNA interference.RNA干扰介导的等位基因特异性沉默
Methods Mol Biol. 2010;623:67-79. doi: 10.1007/978-1-60761-588-0_4.
2
Profiling of mismatch discrimination in RNAi enabled rational design of allele-specific siRNAs.RNAi 中的错配识别分析可实现等位基因特异性 siRNAs 的合理设计。
Nucleic Acids Res. 2009 Dec;37(22):7560-9. doi: 10.1093/nar/gkp835.
3
Assessment of allele-specific gene silencing by RNA interference with mutant and wild-type reporter alleles.通过RNA干扰对突变型和野生型报告基因等位基因进行等位基因特异性基因沉默的评估。
J RNAi Gene Silencing. 2006 Feb 28;2(1):154-60.
4
The pathogenic mechanisms of polyglutamine diseases and current therapeutic strategies.多聚谷氨酰胺疾病的致病机制及当前的治疗策略。
J Neurochem. 2009 Sep;110(6):1737-65. doi: 10.1111/j.1471-4159.2009.06302.x. Epub 2009 Jul 23.
5
Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington's disease patients.针对三个单核苷酸多态性（SNP）的五种小干扰RNA（siRNA）可为四分之三的亨廷顿舞蹈症患者提供治疗。
Curr Biol. 2009 May 12;19(9):774-8. doi: 10.1016/j.cub.2009.03.030. Epub 2009 Apr 9.
6
A majority of Huntington's disease patients may be treatable by individualized allele-specific RNA interference.大多数亨廷顿舞蹈症患者或许可用个体化的等位基因特异性RNA干扰进行治疗。
Exp Neurol. 2009 Jun;217(2):312-9. doi: 10.1016/j.expneurol.2009.03.004. Epub 2009 Mar 13.
7
Molecular cloning and characterization of the common marmoset huntingtin gene.普通狨猴亨廷顿基因的分子克隆与特性分析
Gene. 2009 Mar 1;432(1-2):60-6. doi: 10.1016/j.gene.2008.11.012. Epub 2008 Nov 24.
8
Linking SNPs to CAG repeat length in Huntington's disease patients.将亨廷顿舞蹈症患者的单核苷酸多态性与CAG重复序列长度关联起来。
Nat Methods. 2008 Nov;5(11):951-3. doi: 10.1038/nmeth.1261. Epub 2008 Oct 19.
9
Identification and allele-specific silencing of the mutant huntingtin allele in Huntington's disease patient-derived fibroblasts.亨廷顿舞蹈病患者来源的成纤维细胞中突变型亨廷顿蛋白等位基因的鉴定及等位基因特异性沉默
Hum Gene Ther. 2008 Jul;19(7):710-9. doi: 10.1089/hum.2007.116.
10
Enhancement of allele discrimination by introduction of nucleotide mismatches into siRNA in allele-specific gene silencing by RNAi.在RNA干扰介导的等位基因特异性基因沉默中，通过在小干扰RNA中引入核苷酸错配来增强等位基因鉴别。
PLoS One. 2008 May 21;3(5):e2248. doi: 10.1371/journal.pone.0002248.
Zotero 插件